Invasion of erythrocytes by the malaria parasite is a multi-step process involving several specific interactions between receptors on the red blood cells (RBCs) and specific parasite ligands. Inhibition of RBC invasion by the merozoites would prevent infection and consequently disease. Therefore, identification and characterization of the molecules involved in this process is critical for the develop of new drugs or characterization of the molecules involved in this process is critical for the development of new drugs or vaccines. P. vivax merozoites invade primarily the reticulocytes via a single pathway utilizing in part the Duffy antigen and the P. vivax into reticulocytes. Two other P. vivax reticulocyte-binding proteins were implicated in the specific recognition of the reticulocytes by P. vivax, however, the corresponding reticulocyte receptor(s) have not been identified. We will clone and characterize the reticulocyte receptor(s) and thus support the understanding of the functional relationship of this receptor(s) with the Duffy protein, ultimately helping to establish a transgenic mouse model for P. vivax. P. falciparum was three invasion options involving GPA, GPB and an unknown receptor 'X', of which only the interaction of GP with the parasite ligand EBA- 175 has been well characterized. The P. falciparum ligands that bind specifically to GPB or 'X' and the molecular basis for the alternative pathways of invasion are unknown. Thus, another aim of the proposed research is to identify the receptor(s) 'X' and to clone and characterize the parasite molecules involved in the two alternative pathways of invasion. We will identify receptor(s) 'X' and to clone and characterize the parasite molecules involved in the two alternative pathways of invasion. We will identify novel parasite ligand(s) by evaluating the binding specificity of three newly identified parasite genes containing binding motifs known to function in other BC/parasite interactions, and by isolating biochemically ligands that bind specifically to GPB and receptor(s) 'X'. Followed by cloning. The role of the putative ligands in invasion, and their functional binding domains will be characterized during parasite development in the RBC. To identify receptor 'X' we will use RBC mutants or transformed cells that express trypsin sensitive blood antigens in invasion and binding assays, respectively. The functional binding domains of GBP and receptor(s) 'X' with their corresponding parasite specific ligands will be defined using binding assays and inhibition of binding with specific antibodies or peptides.